Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal motor-neuron neurodegenerative disease. The molecular pathways leading to motor neuron injury and cell death in ALS are incompletely understood. In about 3% of ALS cases, the disease is caused by mutations in the gene encoding the human copper-zinc superoxide dismutase (hSOD1) gene. More than 90 ALS-related mutations in the hSOD1 gene have been identified in familial ALS. These suggested toxic gain of function rather than loss of catalytic hSOD1 activity as the cause of ALS, but the nature of the toxicity has not been determined. Mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) have repeatedly been demonstrated in cells expressing the mutant G93A-hSOD1, an example of such mutations (1-4). These changes mirror alterations in mitochondrial electron transport chain (ETC) activities observed in ALS patients (3,5,6).
Malate dehydrogenases (MDH, L-malate:NAD oxidoreductase, IUBMB Enzyme Nomenclature EC 1.1.1.37) play an important role in mitochondrial respiration. Specifically, they catalyze the NAD/NADH-dependent interconversion of malate and oxaloacetate in the cytoplasm (cytMDH) and mitochondria (MitMDH). This reaction plays a key part in the malate/aspartate shuttle between the cytoplasm across the mitochondrial membrane, and in the tricarboxylic acid cycle within the mitochondrial matrix.
Previous studies have indicated normal or increased malate dehydrogenase (MDH) activity in other neurodegenerative disorders such as Alzheimer's Disease (AD) [Butterworth and Besnard, Metab Brain Dis 1990:5; 179-184, Miulli et al. J Am Osteopath Assoc 1993:93; 670-676, den Velde and Stam, J Am Geriatr Soc 1976:24; 12-16, Sheu et al. Ann Neurol 1985:17; 444-449]. Korolainen et al. [Neurobiol Aging. 2006:27;42-53] discloses increased amounts of mitochondrial glutamate dehydrogenase and cytosolic malate dehydrogenase in AD brains. Furthermore, Korolainen teach that these two enzymes exhibit a significantly decreased degree of oxidation in AD brains compared to controls. [Korolainen et al. Neurobiol Aging. 2006:27;42-53].
A role of MDH in neurodegenerative disease etiology has not been described until now. Rather, changes in MDH activity were considered to be the outcome and not the cause of neurodegeneration. For example, Ferraiuolo et al [Journal of Neuroscience, 2007, 27(34):9201-9219] teaches that amongst the myriad of up-regulated genes, malate dehydrogenase is also upregulated during ALS as detected by microarray analysis. None of the above references disclose or suggest the presence of a MDH complex with a neurodegenerative disease-causing protein or its utility as a therapeutic target for ALS or any neurodegenerative diseases.